Up to 15% of individuals infected with HIV infection develop marked cognitive and motor dysfunction, termed HIV-associated dementia. The introduction of highly active anti-retroviral therapy (HAART) has reduced deaths and the incidence of opportunistic infections, but therapeutic failures occur in about 50%. In many cases, therapeutic failures result from the acquisition of resistance mutations. The impact of HAART on the incidence or course of HIV dementia remains unclear, and the factors underlying variability in treatment response are uncertain. It is likely that durable suppression of CSF HIV levels will be determined by medication adherence and the prevention of anti-retroviral resistance. The CSF pharmacokinetics of anti-retroviral agents and the brain penetration of these agents will also be critical determinants of the successful suppression of CNS infection. Critical questions relating to the use of HAART in treating neurological disease include: first, does the development of anti-retroviral resistance among HIV quasi-species in CSF and brain tissue result in therapeutic failure? Second, do the CSF pharmacokinetics of anti-retrovirals predict therapeutic failure? Third, how does medication adherence, or compliance, influence the durable suppression of CSF HIV levels? All of these factors are potentially important elements of the successful treatment of CNS infection and HIV-D. We will determine the evolution of anti-retroviral resistance in plasma, CSF, and brain compartment in neurologically-characterized HIV-positive individuals initiation HAART. CSF HIV RNA levels will be measured to indicated the adequate long-term suppression of HIV, and related to the CSF pharmacokinetics of anti-retrovirals. Adherence with HAART will be measured using a unique, programmable, device prototype, and the factors influencing incomplete adherence will be studied. These studies will lead to an improved understanding of the relationship between resistance mutations and the durable suppression of CNS HIV infection. The observations relation to anti-retroviral pharmacokinetics and adherence of the CNS will have direct relevance for the design of improve therapies for the prevention and treatment of HIV dementia.